The present invention relates to the preparation of quinoline-substituted carbonate and carbamate derivatives, which provide important intermediates in the synthesis of 6-O-substituted macrolide antibiotics. In one aspect, the invention relates to the processes for preparing quinolyl-substituted carbonate or carbamate compounds and processes for preparing the compounds via an alkenol derivative. In another aspect, the invention relates to preparing carbonate or carbamate compounds via a quinoline carboxaldehyde or a derivative thereof.
6-O-Methylerythromycin A (clarithromycin) is a potent macrolide antibiotic disclosed in U.S. Pat. No. 4,331,803.
The process for making clarithromycin, in general, can be thought of as a four-step procedure beginning with erythromycin A as the starting material:
Step 1: optionally convert the 9-oxo group to an oxime;
Step 2: protect the 2xe2x80x2 and 4xe2x80x3 hydroxyl groups;
Step 3: methylate the 6-hydroxyl group; and
Step 4: deprotect at the 2xe2x80x2, 4xe2x80x3 and 9-positions.
Since the discovery of clarithromycin, new macrolide antibiotic compounds have been discovered and are disclosed in commonly-owned U.S. Pat. No. 5,886,549, filed Jul. 3, 1997. The compounds generally are prepared by known processes. However, the substitution at the 6-position with substituents other than the methyl group is not easy to accomplish and is accompanied by side reactions, by-products and low yields.
Recent developments provide more efficient and cleaner syntheses for alkylating the 6-hydroxyl group. Novel processes allow substituents other than the methyl in the 6-position of the erythromycin derivatives. Commonly-owned U.S. Application Ser. No. 60/149,968, filed on Jun. 24, 1999, discloses a process for preparing 6-O-substituted erythromycin derivatives and for preparing 6-O-substituted erythromycin ketolides involving a palladium catalyzed process using carbonate or carbamate derivatives.
Preparation of the carbonate and carbamate derivatives involve use of a variety of quinoline substituted intermediates. In Chem. Pharm. Bull., 1979, 27(1), 270-273, synthesis of 3-(3-quinolyl)-2-propyn-1-ol is described. However, there are no known reports of quinoline substituted carbonate or carbamate derivatives or the methods of preparing them.
Various methods are disclosed for preparing quinoline-substituted intermediates from which a carbonate, preferably t-butyl carbonate or carbamate compound, is obtained. Processes described and claimed herein employ alcohols, esters, acetals, aldehydes, and carboxylic acids as suitable intermediate compounds. The intermediate compounds provide a suitable substrate from which a quinoline-substituted alkenol is obtained or the intermediate is directly hydrogenated to obtain carbonate or carbamate derivatives of the invention.
In one aspect, the invention relates to a process of preparing a compound of the formula:
R1xe2x80x94CHxe2x95x90CHCH2OC(O)xe2x80x94Xxe2x80x94R2xe2x80x83xe2x80x83(I),
wherein R1 is independently selected from hydrogen and quinolyl optionally substituted with one or more of:
(i) alkyl,
(ii) alkoxy,
(iii) aryl,
(iv) nitro, and
(v) halo;
R2 is C1-C10-alkyl; X is xe2x80x94Oxe2x80x94 or xe2x80x94NR3; and R3 is hydrogen, C1-C6-alkyl or aryl, or R2 and R3 taken together form an aromatic or non-aromatic ring. The process comprises the steps of:
(a) preparing an intermediate selected from the group consisting of:
(i) R1xe2x80x94Cxe2x89xa1CCH2OR4, wherein R4 is hydrogen or a hydroxy protecting group;
(ii) R1xe2x80x94CHxe2x95x90CHC(O)OR5, wherein R5 is C1 to C6 lower alkyl;
(iii) R1xe2x80x94CHxe2x95x90CHCH(OR6)(OR7), wherein R6 and R7 are independently C1 to C6 lower alkyl;
(iv) R1xe2x80x94CHxe2x95x90CHC(O)OH;
(v) R1xe2x80x94CHxe2x95x90CHCHO;
(vi) R1xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94OC(O)xe2x80x94Xxe2x80x94R2; and
(b) reducing or deprotecting an intermediate obtained in step (a); and
(c) optionally coupling the compound obtained from step (b) with an acylating reagent.
Intermediates (i) through (v) can be reduced to provide the alkenol derivative. The alkenol undergoes a coupling reaction with an acylating reagent, for example acyl halides, acid anhydrides, carbamoyl halides, and acid derivatives of aromatic and non-aromatic heterocycles, to afford compounds of formula (I). Intermediate (vi) can be directly hydrogenated to provide compound (I).
Therefore, one process for preparing a compound of formula (I) via the alkenol generally comprises:
(a) preparing a compound of the formula R1xe2x80x94CHxe2x95x90CHCH2OR4, wherein R1 and R4 are as previously defined;
(b) optionally deprotecting the compound obtained in step (a); and
(c) reacting the compound of the formula R1xe2x80x94CHxe2x95x90CHCH2OH with an acylating agent.
An alternative process for preparing the compound of formula (I) comprises:
(a) preparing a compound of the formula R1xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94OC(O)xe2x80x94Xxe2x80x94R2, wherein R1 and R2 are as previously defined; and
(b) hydrogenating the compound obtained in step (a).
In another aspect, the invention relates to a process of preparing a compound of the formula: 
wherein
R1, R2 and X are as previously defined, and R8 is selected from the group consisting of:
(i) xe2x80x94CHxe2x95x90CHxe2x80x94R11; wherein R11 is hydrogen or alkyl; and
(ii) xe2x80x94Cxe2x89xa1CR11.
The process comprises the steps of:
(a) reacting a compound of the formula: 
xe2x80x83wherein X1 is a halide, with an organometallic compound of the formula R8xe2x80x94M or R8xe2x80x94Mxe2x80x94X1, wherein R8 and X1 are as defined above and M is metal, and an acylating reagent;
(b) optionally hydrogenating the compound obtained in step (a), wherein R8 is alkynyl or substituted alkynyl, to afford the corresponding compound wherein R8 is alkenyl or substituted alkenyl.
Yet another aspect of the invention relates to preparing a compound of formula (I) or (II) as defined above.
In yet another aspect, the invention relates to the compounds selected from:
(a) R1xe2x80x94CHxe2x95x90CHC(O)OR5;
(b) R1xe2x80x94CHxe2x95x90CHCH(OR6)(OR7);
(c) R1xe2x80x94CHxe2x95x90CHC(O)OH;
(d) R1xe2x80x94CHxe2x95x90CHCHO;
(e) R1xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94OC(O)xe2x80x94Xxe2x80x94R2; and
(f) R1xe2x80x94CHxe2x95x90CHCH2OH;
wherein R1, R2, R5, R6 and R7 are as previously defined.
Processes of the invention provide carbonate or carbamate compounds useful as intermediates in the synthesis of erythromycin derivatives, for example, macrolide antibiotics and erythromycin ketolide compounds. Compounds of formula (I) or (II) are suitable for preparing 6-O-substituted erythromycin derivatives having a 6-O-quinolyl-substituted propenyl substituent.
A number of terms are used herein to designate particular elements of the present invention. When so used, the following meanings are intended:
The term xe2x80x9clower alkylxe2x80x9d or xe2x80x9calkylxe2x80x9d as used herein refers to straight or branched chain saturated hydrocarbon radicals. xe2x80x9cCx to Cy alkylxe2x80x9d and xe2x80x9cCx-Cyxe2x80x9d, wherein x and y are each an integer from 1 to 20, denotes an alkyl group containing the number of carbons as designated by x and y, for example, the term xe2x80x9cC1 to C6 alkylxe2x80x9d refers to a straight or branched chain saturated hydrocarbon radical containing from 1 to 6 carbon atoms. Exemplary lower alkyl or alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and the like.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to straight- or branched-chain hydrocarbon radicals containing between two and six carbon atoms and possessing at least one carbon-carbon double bond. Examples of alkenyl radicals include vinyl, allyl, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-, 3-, 4-, or 5-hexenyl, and the like, and isomeric forms thereof.
The term xe2x80x9calkynylxe2x80x9d as used herein refers to straight or branched-chain hydrocarbon radicals containing between two and six carbon atoms and possessing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propargyl, propylidyne, and the like, and isomeric forms thereof.
The term xe2x80x9cpolar aprotic solventxe2x80x9d refers to polar organic solvents lacking an easily removed proton including, but not limited to, N,N-dimethylformamide, N,N-dimethyl acetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, and the like, or a mixture thereof.
The term xe2x80x9cacylating reagentxe2x80x9d refers to a substituent capable of placing an acyl group or carbamoyl group onto a nucleophilic site including, but not limited to, acyl halides, acid anhydrides, carbamoyl halides, acid derivatives of aromatic and non-aromatic heterocycles, and the like. Exemplary acylating reagents include, but are not limited to, di-tert-butyl dicarbonate, di-isopropyl dicarbonate, t-butyl chloroformate (not commercially available), 2-(t-butoxycarbonyl-oxyimino)-2-phenylacetonitrile, N-t-butoxy-carbonyloxysuccinimide, 1-(t-butoxycarbonyl)-imidazole, dicyclohexylcarbamoyl chloride, diphenylcarbamoyl chloride, diisopropyl carbamoyl chloride, morpholine acid chloride, carbonyl diimidazole, and the like.
Commonly owned, U.S. Application Serial No. 60/140,968, filed on Jun. 24, 1999, describes a method for preparing 6-O-substituted macrolide derivatives which relates to the coupling of substituted or unsubstituted allyl carbonate or carbamate derivatives with a macrolide core, and particularly a ketolide core. The method exemplifies one method of a number of syntheses available introducing substituted or unsubstituted allyl carbonate and carbamate substituents onto a parent compound core.
Numerous processes for preparing the intermediates and the corresponding carbonate or carbamate compounds therefrom are described herein. Exemplary processes follow in Schemes 1-7, which are intended to illustrate a process of the invention and are not meant to limit the scope of the invention in any way. Isomeric forms of compounds described in the Schemes are contemplated and considered as encompassed within the scope of the claimed invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications are within the purview of the invention and can be made without departing from the spirit and scope thereof.
One manner of preparing the alkenol intermediate involves coupling a propargyl alcohol with a haloquinoline, and reducing the compound obtained therefrom to the corresponding alkenol as exemplified in Scheme 1, below. 
According to Scheme 1, a commercially available haloquinoline (1) wherein X1 is bromine, chlorine, or iodine, is reacted with substituted or unsubstituted propargyl alcohol in the presence of a base and a palladium-based catalyst. The reaction is carried out at a temperature from 20xc2x0 C. to 100xc2x0 C. Preferably, the temperature is from about 25xc2x0 C. to about 90xc2x0 C.
The propargyl alcohol is either unsubstituted or substituted with a hydroxy protecting group R4. The protecting group can be one of many commonly available hydroxy protecting groups. Typical hydroxy protecting groups for R4 include, but are not limited to, tetrahydropyranyl, benzyl, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, formyl, acetyl, pivalyl, mesyl, and tosyl. A thorough discussion of protecting groups and the solvents in which they are most effective is provided by T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Son, Inc., 1999.
At least one carbon of the quinoline-based starting material is substituted with a halide selected from the group consisting of bromine, chlorine, and iodine, for example, bromoquinoline, chloroquinoline, and iodoquinoline. The haloquinoline is optionally substituted with aliphatic or aromatic substituents as well as nitrogen-containing moieties including, but not limited to, alkyl, alkoxy, aryl, and nitro.
The catalyst used is either the 0-valent palladium species or it is generated in-situ, such as palladiumtriphenyl phosphine, by the methods known in the art. See for example, Beller et al. Angew. Chem. Int. Ed. Engl., 1995, 34(17), 1848. The palladium catalyst can be selected from the group consisting of palladium acetate, tetrakis(triphenylphosphine)-palladium, and tris(dibenzylideneacetate)dipalladium.
Treatment with palladium acetate or palladium on carbon proceeds in a facile manner when used with a promoter, preferably a phosphine. A suitable phosphine is selected from triphenylphosphine, bis(diphenylphosphine)methane, bis(diphenylphosphine)ethane, bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, bis(diphenylphosphine)-pentane, tri(o-tolyl)phosphine, and the like. The ratio of palladium catalyst to the phosphine generally ranges from 1:1 to about 1:8.
A halide, such as a copper halide or phase transfer catalyst, such as a tetrabutylammonium halide or tetrabutylammonium hydrogen sulfate, can be used with the palladium-based catalysts to enhance the coupling reation. The preferred copper halides are copper bromide and copper iodide. Preferably, the phase transfer catalyst is tetrabutylammonium bromide.
Useful bases for the invention are organic or inorganic bases. Exemplary inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, and the like, or a mixture thereof.
Organic bases include, but are not limited to, dimethylaminopyridine, pyridine, dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, triethylamine, piperidine, pyrrolidine, pyrrole, triisopropylamine, and the like, or a mixture thereof.
The reaction can be carried out in an aprotic solvent. Typical aprotic solvents are selected from N,N-dimethylformamide, N,N-dimethyl acetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, 1,2-dimethoxyethane, methyl-t-butyl ether, toluene, heptane, acetonitrile and ethyl acetate. The preferred solvent is acetonitrile and N,N-dimethylformamide.
Exemplary conditions in which the reaction is carried out are described below in Table 1.
Conditions described above in Table 1 are meant to be illustrative and are not intended to limit the scope of the invention in any way.
The alkynol (2) obtained from the coupling reaction can be reduced to provide an alkenol (3). The alkynol (2) can be reduced either by catalytic semi-hydrogenation or reduction with an aluminum hydride-type reagent, which respectively produce the cis and the trans isomers of an alkenol intermediate, as illustrated below. 
In Scheme 2, the cis isomer (3-cis) of the alkenol can be prepared by catalytic semi-hydrogenation using hydrogen gas or by catalytic transfer hydrogenation using a hydrogen donor source, such as ammonium formate, formic acid, benzyltriethylammonium formate, hydrazine, cyclohexadiene, and the like, or a mixture thereof. Both methods employ a metal catalyst, such as palladium, platinum, or nickel. Typical catalysts for the semi-hydrogenation include, but are not limited to, bis-dichloro triphenylphosphine palladium(II), palladium acetate, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, palladium on carbon, palladium on calcium carbonate, palladium on barium sulfate, Raney Nickel, and platinum black oxide.
Certain additives are suitable for the catalytic semi-hydrogenation and can afford the cis isomer with improved yields. One suitable additive is 3,6-dithia-1,8-octanediol, however, various other additives can be used in the hydrogenation.
Reacting the alkynol with an aluminum hydride type reagents affords the trans isomer (3-trans). Typically, the reaction is carried out from xe2x88x9220xc2x0 C. to 25xc2x0 C. Aluminum hydride type reagent suitable for the reaction are, for example, lithium aluminum hydride, diisobutylaluminum hydride, or Red-Al (sodium bis(2-methoxyethoxy)aluminum hydride in toluene). About 1 to about 2 molar equivalents of the aluminum hydride are reacted with one equivalent of the 3-(3-quinolyl)-2-propyn-1-ol starting material.
Suitable reaction medium for the aluminum hydride-type reduction is anhydrous tetrahydrofuran. The reaction can also be carried out in polar aprotic solvents, such as dimethoxyethane or methyl-t-butyl ether, and nonpolar aprotic solvents, such as toluene.
When R4 of the alkenol is a hydroxy protecting group, the compound is deprotected prior to converting the alcohol to a carbonate or carbamate moiety. Deprotection of the hydroxy group can be accomplished under acidic or basic conditions depending on the nature of the protecting group by standard methods known in the art. A summary of the procedures suitable for deprotecting the hydroxy group is described in T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Son, Inc., 1991, which is herein incorporated by reference.
Conversion of alkenol (3) to the carbonate or carbamate derivatives can be carried out with a wide variety of reagents. The product mixture obtained maintains the approximate proportions of cis to trans isomers which indicates the conversion preserves the orientation at the regiocenter as shown below. 
According to Scheme 3, an acylating reagent is reacted with a quinoline-substituted alkenol (3-cis or 3-trans) obtained from the reduction reaction to convert the alcohol to a desired carbonate or carbamate derivative of formula (I), the cis and trans isomers of which correspond to compounds (4-cis) and (4-trans), wherein X is xe2x80x94Oxe2x80x94 and R2 is C1-C10-alkyl, respectively. The reaction is carried out in an aprotic solvent at temperatures from about xe2x88x9230xc2x0 C. to 50xc2x0 C. Introducing either an organic or an inorganic base facilitates the reaction.
The acylating reagent places group of the formula 
wherein X and R2 are as previously defined, onto the oxygen atom of the hydroxy moiety. Acylating reagents suitable for preparing the carbonate derivatives are typically acyl halides and acid anhydrides, which include, but are not limited to, di-tert-butyl dicarbonate and di-isopropyl dicarbonate. Other exemplary reagents include are t-butyl chloroformate, 2-(t-butoxy-carbonyloxyimino)-2-phenylacetonitrile, N-t-butoxycarbonyloxy-succinimide, and 1-(t-butoxy-carbonyl)imidazole, and the like. For preparing the preferred carbonate, 3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate the 3-(3-quinolyl)-2-propen-1-ol intermediate is preferably treated with di-tert-butyl dicarbonate.
Carbamate derivatives of formula (I) can be prepared by reacting the alkenol, with a suitable carbamoyl chloride or the acid chloride of an aromatic or non-aromatic nitrogen heterocycle in the presence of base. Exemplary acylating reagents for preparing the carbamate compounds are selected from carbamoyl halides and acid derivatives of aromatic and non-aromatic nitrogen containing heterocycles, including but not limited to, dicyclohexylcarbamoyl chloride, diphenylcarbamoyl chloride, diisopropyl carbamoyl chloride, morpholine acid chloride, carbonyl diimidazole, and the like.
Aprotic solvents are selected from the group as described above. The preferred solvent is toluene. Dichloromethane is also suitable for the reaction. Conversion of the alkenol proceeds in a more facile manner when from about 0.01 to about 0.05 molar equivalents of a phase transfer reagent relative to the alkenol starting material is added to the reaction mixture. A wide variety of phase transfer reagents are suitable for the reaction including, but not limited to, n-tetrabutylammonium halides and n-tetrabutylammonium hydrogen sulfate. The preferred phase transfer reagent is n-tetrabutylammonium hydrogen sulfate.
Alternatively, the alkynol (2) is coupled with the acylating reagent to afford a carbonate or carbamate intermediate of the formula R1xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94OC(O)xe2x80x94Xxe2x80x94R2, wherein R1 and R2 are previously defined, which can be reduced to provide the alkenyl carbonate or carbamate compounds of formula (I). The intermediate can be reduced by way of catalytic semi-hydrogenation to provide the derivative of formula (I). Preferably, the intermediate is reduced using 5% palladium on calcium carbonate poisoned with lead (Lindlar""s catalyst, Pd/CaCO3/Pb) and hydrogen gas, which provides the cis isomer (3-cis). The portion of Lindlar""s catalyst reacted with one equivalent of the alkynol starting material is from about 0.005 to about 0.2 weight/weight equivalents.
One alternate method of preparing the carbonate relates to treating a haloquinoline with propargyl alcohol, a copper halide, or more preferably copper iodide, and dichlorobis-(triphenylphosphine)palladium(II) in the presence of triethylamine in an aprotic solvent. The alkynol obtained therefrom is reduced by methods of hydrogenation or Red-Al reduction to afford an alkenol, which can be coupled with an acylating agent to provide a desired derivative.
Another preferred method of preparing the alkynol involves reacting a haloquinoline with propargyl alcohol, tetrabutylammonium bromide, and palladium acetate or palladium on carbon in combination with a phosphine. The reaction is accomplished in the presence of a secondary amine, such as piperidine, or acetonitrile or mixtures of THF and water. Reduction of the alkynol with Red-Al is accomplished with tetrahydrofuran solvent and the resulting alkenol is coupled with an acylating reagent, such as di-tert-butyl dicarbonate, in the presence of base and tetrabutylammonium hydrogen sulfate in dichloromethane or toluene.
Preferably, the haloquinoline starting material is selected from 3-bromoquinoline or 3-iodoquinoline. The most preferred haloquinoline is 3-bromoquinoline.
Other possible methods for preparing the alkenol involve using acrolein acetal or vinyl ester reagents as described in the following Scheme. 
As illustrated in Scheme 4, a haloquinoline couples (1) with an acrolein acetal (7) having a formula CH2xe2x95x90CHCH(OR6)(OR7), wherein R6 and R7 are independently C1 to C6 alkyl, via a palladium-catalyzed reaction in the presence of a base. The reaction is carried out at a temperature from about 90xc2x0 C. to about 110xc2x0 C. in a polar aprotic solvent.
Palladium catalysts suitable for coupling the propargyl alcohol with the haloquinoline can also be used for the reacting the starting material with the acrolein acetal. Acrolein acetals suitable for the coupling include, but are not limited to, acrolein dimethylacetal, acrolein diethylacetal, acrolein diisopropylacetal, acrolein n-dibutylacetal, acrolein n-dipentylacetal, acrolein ethylmethylacetal, acrolein isopropylmethylacetal, and the like. Portions of the acrolein acetal used relative to the haloquinoline generally ranges from about 1:1 to about 4:1
A phosphine is optionally used with the palladium acetate catalyst. Suitable phosphines are selected from the group as described above relating to the coupling of the alkynol in Scheme 1. Preferably, the phosphine for coupling the acrolein acetal with the haloquinoline is tri(o-tolyl)phosphine. Portions of the phosphine relative to portions of the palladium catalyst generally range from about 1:1 to about 8:1.
Addition of a phase transfer agent, preferably tetrabutylammonium hydrogen sulfate, provides the carbonate.
An inorganic or organic base is suitable for the reaction, and selected from the group described above. The reaction is carried out in an aprotic solvent as previously described.
The carboxaldehyde acetal (8) wherein R6 and R7 are independently C1 to C6 alkyl, obtained therefrom is then treated with an acid to produce the acrolein (9). The acid is selected from a wide variety of inorganic and organic acids selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid, propionic acid, butyric acid, tartaric acid, citric acid, trifluoroacetic acid, p-toluensulfonic acid, pyridinium p-toluenesulfonic acid, and the like, or a mixture thereof.
The preparation of the acrolein allows for using milder reducing agents, such as borane complex reagents, during reduction. Reduction of the acrolein with a borane complex reagent provides the alkenol, which can be converted into the carbonate or carbamate derivatives of formula (I) as previously described. The reduction is accomplished at room temperature in an aprotic solvent selected from the group described above for the coupling the alkynol to the haloquinoline. Exemplary borane complex reagents include, but are not limited to, borane-dimethyl sulfide, borane-tetrahydrofuran complex, borane-pyridine complex, borane-morpholine, borane-trimethylamine complex, borane t-butylamine, borane-N,N-diisopropylethylamine, borane dimethylamine, 4-(borane-dimethylamino)pyridine, borane-4-ethylmorpholine, and borane-4-methylmorpholine. From about 0.25 to about 1 equivalent of borane complex is reacted with 1 equivalent of the 3-(3-quinolyl)acrolein. The most preferred borane complex reagent is borane t-butylamine.
Similarly, borohydride reducing reagents are suitable for the reaction. Typical borohydride reducing reagents are selected from borane, borane-methyl sulfide, borane-methylsulfide with additives such as BF3.OEt2 or B(OMe)3, 9-borabicyclononane, lithium borohydride, sodium borohydride alone or with additives such as AlCl3 or TiCl4, lithium borohydride, and potassium borohydride.
Aluminum hydride reducing reagents, for example diisobutyl aluminum hydride and lithium aluminium hydride alone or with AlCl3, are also suitable for the reduction.
The palladium coupling reaction can also be carried out using a vinyl ester (10) of the formula CH2xe2x95x90CHC(O)OR5, wherein R5 is C1 to C6 alkyl, for preparing 3-(quinolyl-substituted)-2-propen-1-alkyl ester (11), wherein R5 is C1 to C6 alkyl. Treating a haloquinoline with a vinyl ester and palladium acetate yields the alkyl ester absent the use of a phosphine. The reaction is carried out in an aprotic solvent in the presence of base with the addition of a phase transfer reagent, such as tetrabutylammonium bromide or tetrabutylammonium chloride.
Exemplary vinyl esters suitable for the reaction include, but are not limited to, methyl acrylate, ethyl acrylate, and the like.
The alkenol starting material for the conversion reaction is obtained from the alkyl ester in one of two ways. Direct reduction of the alkyl ester with an aluminum hydride reagent as detailed above in Scheme 1 provides the alcohol under conditions as previously described. Treating the alkyl ester (11) at ambient temperature with from about 1 to about 10 molar equivalents of base for each equivalent of the alkyl ester affords carboxylic acid (12), which can be further reduced to the alcohol under mild reduction conditions with a boron reducing reagent, such as borohydrides or borane complex reducing agents.
Various processes yield secondary carbonate derivatives, which are described in accordance with another aspect of the invention. The compounds of the formula: 
wherein R1 is independently selected from hydrogen and quinolyl optionally substituted with one or more of (i) alkyl, (ii) alkoxy, (iii) aryl, (iv) nitro, and (v) halo; R2 is C1-C10-alkyl; X is xe2x80x94Oxe2x80x94 or xe2x80x94NR3, wherein R3 is hydrogen, C1-C6-alkyl or aryl, or R2 and R3 taken together form an aromatic or non-aromatic ring; and R8 is xe2x80x94CHxe2x95x90CHxe2x80x94R11 or xe2x80x94Cxe2x89xa1CR11, wherein R11 is hydrogen or alkyl; can be used as intermediates in the 6-O-alkylation of macrolide antibiotic and ketolide compounds. Alkylation of the 6-O-position of an erythromycin derivative is accomplished in a manner similar to the synthesis using the primary carbonate, as described in the U.S. Application Ser. No. 60/140,968.
The secondary carbonate or carbamate derivatives can be prepared by one of at least two syntheses. In one method, a 2-halo-quinoline-3-carboxaldehyde starting material is treated with an organometallic reagent and an acylating agent to obtain a compound of the desired formula. In another method, a quinoline carboxaldehyde is reacted with an organometallic reagent followed by treatment with an organolithium compound. The compound is reacted with acylating reagent to provide compounds of formula (III), as illustrated below. 
A 2-halo-3-quinoline carboxaldehyde (13 ) can be reacted with an organometallic reagent R8xe2x80x94M or R8xe2x80x94Mxe2x80x94X1, wherein R8 is as defined above, M represents a metal, and X1 is a halide, and treated with an acylating reagent to provide a protected secondary carbonate. Preferably, the haloquinoline carboxaldehyde is 2-iodo-3-quinoline carboxaldehyde. Reaction with the organometallic reagent is accomplished in an aprotic solvent. Exemplary organometallic reagents are vinyl magnesium bromide, vinyl magnesium chloride, and the like. A suitable lithium reagent can be reacted with the product obtained therefrom and followed by a suitable acylating reagent to provide the secondary carbonate.
Suitable organolithium reagents are alkyl lithium reagents. The preferred alkyl lithium reagent is n-butyllithium.
Reaction of an organometallic reagent with a quinoline carboxaldehyde (14) and an acylating reagent affords compounds of formula (III). The preferred reagent, quinoline-3-carboxaldehyde, is a commercially available compound. However, the cost for the material is expensive ($230/5 g, Aldrich, Milwaukee, Wis., U.S.A.). Novel processes for preparing the starting material provide a more efficient and cost effective synthesis and can be used for the preparation of a quinoline carboxaldehyde material or in accordance with a process for preparing quinoline-substituted carbonate, as illustrated below. 
The starting material for the carboxaldehyde synthesis (13), wherein X1 is a halide, can be prepared by Vilsmeier-Haack formylation of an acetanilide as described by Meth-Cohn, et al. in J. C. S. Perkin I, 1520-1530 (1981). The quinoline-2-halo-3-carboxaldehyde is isolated and dried to obtain the starting material or, alternatively, an alcohol or orthoformate reagent is directly charged into the reaction mixture to obtain the quinoline-2-halo-3-carboxaldehyde acetal (16), wherein R9 and R10 are independently C1 to C6 alkyl.
Reagents useful for the reaction are alcohols represented by the formula R9xe2x80x94OH or orthoformates represented by the formula HC(OR10)3, wherein R9 is C1 to C6 alkyl and R10 is C1 to C3 alkyl. An alcohol suitable for the invention is selected from methanol, ethanol, isopropanol, butanol, pentanol, and hexanol, or a mixture thereof. Examples of useful orthoesters are trimethyl orthoformate, triethyl orthoformate, triisopropyl orthoformate, and the like. Trace amounts of organic or inorganic acid facilitate the conversion, such as those typically selected from acetic acid, formic acid, p-toluenesulfonic acid, hydrochloric acid, phosphoric acid, sulfuric acid, and the like.
Removing the halo group of the quinoline-2-halo-3-carboxaldehyde acetal is accomplished by treatment with a metal catalyst and hydrogen in the presence of a base. The metal catalysts include, but are not limited to, palladium, organopalladium, and platinum-based compounds. Examples of suitable metal catalysts are palladium black oxide, palladium on charcoal, palladium acetate, palladium chloride, triarylphosphine palladium complexes, platinum black oxide, and the like. A summary of suitable reagents and conditions for metal-catalyzed coupling reactions are described in Heck et al., J. Org. Chem., 1972 37, 2320.
The reaction is carried out in an organic solvent in the presence of from about 1 to about 6 molar equivalents of base relative to the carboxaldehyde acetal starting material. Preferably, about 4 molar equivalents of base is used. Exemplary solvents used are organic solvents, such as acetonitrile, N,N-dimethylformamide, N-methylpyrrolidinone, methanol, ethanol, isopropanol, and the like, or a mixture thereof. Organic base, for example amines, and inorganic bases are suitable for the reaction. Amines that are useful include, but are not limited to, secondary and tertiary amines, such as dimethylamine, diethylamine, triethylamine, diisopropylethylamine, diethylaminopyridine, and pyridine. Inorganic bases are selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, and the like.
The carboxaldehyde (14) is obtained from carboxaldehyde acetal (17) by hydrolysis with an acid carried out in organic or inorganic solvent. The acids are organic and inorganic acids. Suitable inorganic acids include sulfuric acid, hydrochloric acid, and the like. The preferred solvents are organic solvents, such as methanol, ethanol, isopropanol, and the like. Preferably, the weak acids are formic acid and acetic acid.
The carboxaldehyde provides a suitable starting material for the synthesis of the primary and secondary carbonate derivatives. The addition of an organometallic reagent compound to the carboxaldehyde generates an intermediate complex, which is coupled to an acylating reagent, for example di-tert-butyl dicarbonate and di-isopropyl dicarbonate, to prepare a carbonate. Other exemplary acylating reagents are as described above. Carbamate derivatives of the invention can be prepared by using carbamoyl chlorides or acid chlorides of aromatic or non-aromatic nitrogen heterocycles.
Suitable organometallic reagents are represented by the formula R8xe2x80x94M and R8xe2x80x94Mxe2x80x94X1, wherein R8 is substituted or unsubstituted C1-C6 alkenyl or C1-C6 alkynyl, such as substituents of the formula xe2x80x94CHxe2x95x90CHxe2x80x94R11 and xe2x80x94Cxe2x89xa1Cxe2x80x94R11, wherein R11 is hydrogen or alkyl, M represents a metal, and X1 is a halide. Preferably, the organometallic reagent used is an organolithium or an organomagnesium reagent, such as a Grignard reagent. The preferred reagents are selected from reagents of the formulas R8xe2x80x94M and R8xe2x80x94Mxe2x80x94X1, wherein M is lithium or magnesium and X is bromine, chlorine, and iodine. Common Grignard reagents as described in accordance with the Y. H. Lai, Synthesis 1981, 104, which is herein incorporated by reference. Exemplary organometallic reagents are t-butyl lithium, diethylmagnesium, ethynylmagnesium bromide, ethynylmagnesium chloride, vinylmagnesium bromide, vinylmagnesium chloride, and the like.
The reaction is accomplished in an aprotic solvent selected from the group described above for the preparation of the alkynol. Suitable temperatures for the reaction are from about xe2x88x9210xc2x0 C. to about xe2x88x9215xc2x0 C.
Alkyne-1-substituted quinoline compounds of formula (II), wherein R8 is xe2x80x94Cxe2x89xa1Cxe2x80x94R11 can be optionally reduced to the corresponding alkenyl-substituted carbonate by a palladium-catalyzed hydrogenation reaction using hydrogen gas. The preferred palladium catalyst for reducing the alkyne-1-substituted quinoline carbonate is Lindlar""s catalyst (5% palladium on calcium carbonate poisoned with lead or Pd/CaCO3/Pb).
The reaction is carried out in a polar organic solvent selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, and isopropanol.
The carboxaldehyde (14) can also undergo condensation with an acetate ester (18), wherein R5 is C1 to C6 alkyl, with either an organic or inorganic base to provide a primary carbonate or carbamate, which is describe in accordance with the Scheme 7 below. 
A suitable acetate ester for the reaction is represented by the formula H3Cxe2x80x94C(O)(OR5), (18) wherein R5 is C1 to C6 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, and the like. Preferably, about 0.5 molar equivalents to about 2 molar equivalents of base are used relative to the carboxaldehyde. Typical bases for the reaction include, but are not limited to, potassium t-butoxide, sodium t-butoxide, sodium hydride, potassium carbonate, sodium ethoxide, sodium methoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, and the like. Potassium t-butoxide is the preferred base.
Condensation of acetaldehyde with the carboxaldehyde (14) affords the acrolein intermediate (9) using relatively inexpensive reagents. The condensation can be carried out with acetic anhydride in the presence of an acid. Reduction of the product obtained therefrom provides the corresponding alkenol. The preferred method for reducing the acrolein intermediate is reduction with a borohydride reagent, such as sodium borohydride.
The processes described for the invention are particularly useful for preparing 3-(3-quinolyl)-2-propenyl derivatives, which are compounds of formula (I) and have the preferred structure for the 6-O-allylation reaction of macrolide antibiotics. To obtain 3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate, for example, 3-bromoquinoline is coupled with propargyl alcohol, and reduced by methods of catalytic semi-hydrogenation to obtain 3-(3-quinolyl)-2-propen-1-ol. The 3-(3-quinolyl)-2-propen-1-ol is coupled with an acylating reagent capable of placing a t-butyl group on the oxygen atom of the terminal hydroxy group, preferably di-tert-butyl dicarbonate, to afford 3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate.
In another preferred process, the 3-(3-quinolyl)-2-propyn-1-ol is coupled with an acylating reagent to provide a carbonate or carbamate derivatives, which can be hydrogenated to provide a compound of formula (I). The preferred acylating reagent for the reaction is di-tert-butyl dicarbonate.
In yet another preferred process, the 2-chloro-3-quinoline carboxaldehyde is converted into 2-iodo-3-quinoline and reacted with vinyl magnesium bromide followed by n-butyllithium and an acylating agent, preferably di-tert-butyl dicarbonate. The 1-(3-quinolyl)-2-propen-1-ol t-butyl carbonate prepared by the process is a compound of formula (II).
The processes for preparing a compound of formula (I) via the alkenol intermediate can be generally described as comprising the steps of:
(a) preparing a compound of the formula R1xe2x80x94CHxe2x95x90CHCH2OR4, wherein R1 and R4 are as previously defined;
(b) optionally deprotecting the compound obtained in step (a); and
(c) reacting the compound of the formula R1xe2x80x94CHxe2x95x90CHCH2OH with an acylating agent.
An alternative process for preparing the compounds of formula (I) comprises:
(a) preparing a compound of the formula R1xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94OC(O)xe2x80x94Xxe2x80x94R2, wherein R1 and R2 are as previously defined; and
(b) hydrogenating the compound obtained in step (a).
The alternative process allows for preparation of the carbonate and carbamate derivatives by directly coupling a propargyl alcohol derivative with an acylating reagent and hydrogenating the alkyne bond to obtain a desired compound.
In another aspect, the invention relates to a compound having the formula
R1xe2x80x94CHxe2x95x90CHCH2OC(O)xe2x80x94Xxe2x80x94R2xe2x80x83xe2x80x83(I)
or 
wherein
X is xe2x80x94Oxe2x80x94 or xe2x80x94NR3xe2x80x94;
R1 is independently selected from hydrogen and quinolyl optionally substituted with one or more substituents selected from:
(i) alkyl,
(ii) alkoxy,
(iii) aryl,
(iv) nitro, and
(v) halo;
R2 is C1-C10-alkyl;
R3 is hydrogen or C1-C6-alkyl; or R2 and R3 taken together form an aromatic or non-aromatic ring; and
R8 is selected from:
(i) xe2x80x94CHxe2x95x90CHxe2x80x94R11; and
(ii) xe2x80x94Cxe2x89xa1CR11, wherein R11 is hydrogen or alkyl.
The invention also relates intermediate compounds having the formula:
(a) R1xe2x80x94CHxe2x95x90CHC(O)OR5, wherein R1 is independently selected from hydrogen and quinolyl optionally substituted with one or substituent selected from (i) alkyl, (ii) alkoxy, (iii) aryl, (iv) nitro, and (v) halo; and R5 is C1 to C6 lower alkyl;
(b) R1xe2x80x94CHxe2x95x90CHCH(OR6)(OR7), wherein R6 and R7 are independently C1 to C6 alkyl;
(c) R1xe2x80x94CHxe2x95x90CHC(O)OH;
(d) R1xe2x80x94CHxe2x95x90CHCHO;
(e) R1xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94OC(O)xe2x80x94Xxe2x80x94R2; wherein R2 is C1-C10-alkyl; X is xe2x80x94Oxe2x80x94 or xe2x80x94NR3; and R3 is hydrogen, C1-C6-alkyl or aryl; or R2 and R3 taken together form an aromatic or non-aromatic ring; or
(f) R1xe2x80x94CHxe2x95x90CHCH2OH.
The intermediates are prepared by processes previously described and provide useful compounds in obtaining the desired carbonates and carbamates of formulas (I), (II) and (III).
Processes of the invention are better understood by reference to the following Reference Example and Examples. Various changes and modification may be made by one having ordinary skill in the art without departing from the scope of the invention. The Reference Example and the Examples are intended to provide illustration for a better understanding of the invention and are not meant to limit the invention in any way.